One important strategy in designing effective cancer chemotherapeutic drugs is defining the mechanism of cell death. Activation of the chromatin-bound enzyme, adenosine diphosphate ribosyl transferase (ADPRT), and the subsequent depletion of energy metabolites, such as NAD and ATP, are involved in the suicidal response to induced cellular DNA damage that leads eventually to cell death, Berger, N. A., J. Clin. Invest. 78:1131-1135, 1986.
Radiation and/or most cancer therapeutic drugs induce DNA damage, and as a consequence involve ADPRT activity as part of their cytotoxic mechanisms of action, Huet and Laval, Int. J. Radiat. Biol. 47: 655-662, 1985.
Hence, inducers of ADPRT enhance cytotoxicity by seriously depleting cellular energy pools in an effort to repair the potentially lethal DNA damage induced by most chemotherapeutic drugs and/or radiation. This is true because NAD is consumed as a co-substrate by ADPRT activity, Hayaishi and Ueda, Ann. Rev. Biochem. 46:96-116, 1977; Purnell et al, Biochem. Soc. Trans. 8:215-227, 1980which is in turn, induced by DNA strand breaks, Halldorsson et al. FEBS Lett. 85:349-352, 1978; Benjamin and gill, J. Biol, Chem. 255:10493-10508, 1980; Cohen and Berger, Biochem. Biophys. Res. Commun. 98: 268-274, 1981. Since cellular NAD/ATP pools are coupled, then cellular energy is depleted and cytotoxicity is enhanced. On he other hand, inhibitors of ADPRT are also sensitizers of cytotoxicity because they prevent the repair of potentially lethal DNA damage.